Histone deacetylase (HDAC) inhibitors are a diverse group of molecules that can induce growth arrest, differentiation, apoptosis and autophagocytic cell death of cancer cells. Hence, HDAC inhibitors are prime agents for the development of novel anticancer drugs. One HDAC inhibitor, Zolinza (vorinostat or suberoylanilide hydroxamic acid—SAHA), was recently approved by the U.S. Food and Drug Administration, and at least nine other HDAC inhibitors, including FK228, are in various stages of clinical trials.
FK228 (C24H36N4O6S2; molecular weight, 540.2) (FIG. 1), also known as FR901228 or depsipeptide and registered as NSC 630176 or romidepsin, is a natural product discovered in the fermentation broth of Chromobacterium violaceum No. 968 in a screening program for agents that reverse the malignant phenotype of a Ha-ras oncogene-transformed NIH 3T3 cell line (Ueda, Nakajima et al. 1994; Ueda, Nakajima et al. 1994). FK228 exhibits anticancer activities against an array of tumor cell lines, including many members of a standard panel of 60 cell lines from the U.S. National Cancer Institute (Vigushin 2002; Garber 2007). In clinical trials, FK228 has shown promise as an anticancer drug (NCI 2008).
Structurally, FK228 is a bicyclic depsipeptide that features a 16-membered macrolactone ring containing an ester linkage and a 17-membered ring containing the same ester linkage and a disulfide bond (FIG. 1). Its structure was determined by spectroscopic and X-ray crystallographic analyses (Shigematsu, Ueda et al. 1994) and was confirmed by total synthesis (Li, Wu et al. 1996). Its intramolecular disulfide bond makes FK228 structurally distinct from other known HDAC inhibitors, such as hydroxamic acids, apicidin and trapoxin. FK228 serves as a stable prodrug that is converted to its active form by intracellular reduction of the disulfide bond after uptake into the cells or organisms. The freed sulfhydryl group on the longer aliphatic tail of reduced FK228 fits inside the catalytic pocket of preferred class I HDACs, chelating Zn2+, thus inhibiting HDAC activity (Furumai, Matsuyama et al. 2002).
Despite its promise as an anticancer agent, efforts to obtain large quantities of FK228 have been hampered because native production of FK228 from Chromobacterium violaceum No. 968 is relatively limited, and total synthesis of FK228 has proven difficult (Li, Wu et al. 1996). Due to its anticancer activities and novel structural characteristics, FK228 may serve as a molecular scaffold to generate structural analogs, from which additional compounds with therapeutic properties may be developed.
Thus, there is a need in the art for compositions and methods for synthesizing FK228 and FK228 analogs.